Κυριακή, 23 Ιουλίου 2017

CDK4/6 INHIBITORS ARE WELL TOLERATED

A class of oral drugs for treating breast cancer known as cyclin-dependent kinase (CDK) 4/6 inhibitors are generally well-tolerated, with a manageable toxicity profile for most patients. This is the conclusion of a comprehensive review of toxicities and drug interactions related to this class of drugs, published by Spring et al in The Oncologist.
The excitement surrounding CDK4/6 inhibitors is due to their potential for treating hormone receptor–positive metastatic breast cancer, the most common form of the disease. The first CDK4/6 inhibitors were recently approved by the U.S. Food and Drug Administration (FDA), with palbociclib (Ibrance) approved in February 2015 and ribociclib (Kisqali) approved in March 2017. A third, abemaciclib, is currently undergoing phase III trials. All three CDK4/6 inhibitors have received Breakthrough Therapy designation from the FDA.
“CDK inhibitors have changed the landscape of management of hormone receptor–positive breast cancer,” said Aditya Bardia, MBBS, MPH, a specialist in breast cancer at the Massachusetts General Hospital Cancer Center and  senior and corresponding author on the article.
A major hallmark of cancer cells is their ability to multiply rapidly; CDK4/6 inhibitors interfere with this process by blocking the activity of enzymes known as CDKs (particularly CDK4 and CDK6) that help to regulate cell division. For effectively treating breast cancer, CDK4/6 inhibitors are usually combined with endocrine therapy, which works by preventing hormones from binding with their respective receptors on the cancer cells.
“Given the excitement with these drugs, there has been considerable uptake in clinical practice for management of patients with metastatic breast cancer,” explained Dr. Bardia. “However, these agents are different from endocrine therapies, and have a unique set of side effects. Therefore, we felt it was important to have a dedicated review article on clinical management of potential toxicities and drug interactions seen with the use of CDK4/6 inhibitors and summarize practical management strategies for a medical oncologist.”
Review Findings
Dr. Bardia and his team reviewed all the publicly available studies conducted on palbociclib, ribociclib, and abemaciclib, most of which had formed part of the approval process for these drugs. For palbociclib and ribociclib, the most common side effect was neutropenia, which can increase the chance of infection. CDK4/6 inhibitors are known to affect the division of blood cells in the bone marrow, including white blood cells. However, since the impact on white blood cells is temporary and dose-dependent, the counts usually return to normal with dose-interruption or dose-reduction of palbociclib or ribociclib.
While all the CDK4/6 inhibitors affect the cell-cycle, there are slight differences between them. For example, neutropenia appears to be less common with abemaciclib; other side effects such as diarrhea and fatigue appear to be more common. Various other, less common side effects are sometimes also seen with CDK4/6 inhibitors, including nausea and alopecia, but are usually mild and can often be treated by reducing the dose and taking regular breaks.
Dr. Bardia and his team cautioned that patients and treating physicians should be aware of certain drug-drug interactions with CDK4/6 inhibitors, particularly for substances that inhibit the activity of an enzyme known as CYP3A, such as the antibiotic clarithromycin and grape juice. This is because CYP3A is the prime enzyme responsible for breaking down CDK4/6 inhibitors in the liver, and thus inhibiting its activity could lead to the build-up of high levels of the drug.


CDK4/6 inhibitors are now being investigated for their ability to treat various other cancers, including lung cancer, prostate cancer, and ovarian cancer, so their efficacy and excellent safety profile could eventually prove to have benefit in diseases besides breast cancer.

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